Born after normal pregnancy; intractable seizures on the first day of life. Also acquired microcephaly, severe developmental delay, a seizure disorder, and marked visual impairment. At 3y acquired microcephaly; head circumference 44 cm (<3rd centile), height 89 cm (10%), weight 13.1 kg (25%). No dysmorphic features, no organomegaly, with normal skin and extremities. Neurological examination: profound cognitive and gross motor impairment; no persistent primitive reflexes an overall developmental age of less than 4 months; normal routine blood work and cerebrospinal fluid analysis; ophthalmologic exam: optic atrophy, poor vision, and optical oscillation. Somatosensory evoked potential, brainstem auditory evoked potential, and peripheral nerve conduction were normal. Head MRI showed diffuse hyperintensity on T2-weighed images early on but there was interval maturation of myelination with only mild delay in myelination at age 3 years. There was under-operculation with simplification of the gyri in the frontal lobe, and thin corpus callosum suggesting cerebral dysgenesis. Bone films of spine showed thoraco-lumbar scoliosis.

As newborn child seemed normal. Later in childhood, developmental delay, particularly of language skills. At 15y height >95th centile, high forehead, down-slanting palpebral fissures, wide diastema between upper incisors, high palate, short fraenulum of the upper lip, prominent lips and scoliosis, long and tapering fingers, fifth finger campodactyly, hallux valgus, fifth toe clinodactyly, pes planus. Overall neuropsychological picture: borderline intelligence with specific cognitive deficits in the processing of verbal information as well as learning disorders. Brain magnetic resonance imaging: enlarged cisterna magna with slight hypoplasia of the basal part of the cerebellar hemispheres as well as of the inferior vermis; the posterior fossa was normal.

Born at 39 weeks gestation after a pregnancy with gestational diabetes and a delivery reported to be prolonged; birth weight was 3950g. Hypertonia was noticed from birth and continued throughout the first 6 months of life; Significant for motor and cognitive developmental delay identified from early infancy. At 31, 36 and 60 months of age he had the developmental age of 18, 20 and 30 months, respectively. He gained speech skills at 6 years of age and currently, his cognitive skills are very limited, with poor learning and speech abilities; limited social interactions; mild dysmorphic features including macrocranium, round face, upslanting eyes and thick auricles Brain CT and MRI performed revealed cortical atrophy, partial agenesis of the corpus callosum and mild changes in the white matter in the occipital lobes; several generalized tonic-clonic seizures started at 1 year of age. EEG and video-EEG performed at the first and third years of life showed waves and spikes from foci in both hemispheres with a few generalized bursts, and slow background activity. Growth pattern was characterized by height at the 50th percentile over the first 2 years of life and along the 90th percentile thereafter, with head circumference at the 90th percentile from infancy; most prominent growth feature was a remarkable weight gain: BMI 33.5, 44, 46 and 51 at 5, 8, 10 and 12 years of age, respectively. Subsequent to morbid obesity, he developed several co-morbidities:(1) hypercholesterolemia (2) moderate elevations in liver transaminase levels, (3) hyperuricemia that responded to a short-term treatment with allopurinol; (4) a mild degree of pulmonary hypertension, documented by echocardiography; and (5) Pickwickian syndrome, manifested by night snoring, daytime somnolence and episodes of sleep apnea. At about 13 years of age the patient started pubertal maturation, and currently (at 14 years of age) he is in Tanner pubertal stage.

Twins born in week 35 of gestation, mild neonatal jaundice; normal at birth; at 5m twin II had a generalized tonic-clonic seizure associated with fever; at 6m other similar seizures without feaver; at 22m she was found dead in her cot and was presumed to have had a prolonged seizure. In Twin I eyelid twitching and flickering at 6m and seizures subsequently. developmental delay occurred and lost of ability to walk unaided at 18m. OFC always on 90. centile; abnormal EEG; developmental delay; died at 4y8m due to a prolonged status epilepticus (4h)

19-CW-3

male/ prenatal

AF

de novo

47,XY,+mar[27]/ 46,XY[23]

r(19)

D1Z7/D5Z2/D19Z3; wcp 19

see below

{14} case 3

Amniocentesis due to abnormalities identified on ultrasound: oligohydramnios, clubfoot and increased nuchal thickness. parents elected to terminate the pregnancy.

Amniocentesis due to advanced maternal age; no ultrasound abnormalities in week 15; spontaneous abortion after amniocentesis

19-U-3

male/ prenatal

AF

de novo?

47,XY,+mar[100%]

r(19)(::p12→q12::)

midi

n.a.

{9} case 4

19-U-4

male/ prenatal

AF

de novo

47,XY,+r[17%]/ 46,XY[83%]

r(19)

centromeric probes and wcp

pregnancy terminated; autopsy result normal

{10} case 5

19-U-5

female/ prenatal

AF

de novo

47,XX,+mar[10%]/ 46,XX[90%]

min(19)(:p13.11→q12:)

cenM; subcenM

see below

{0} provided by Dr. Klein, Butzbach, Germany

Amniocentesis due to advanced maternal age; no ultrasound abnormalities; pregnancy was terminated - no additional information available

19-U-6

male/ prenatal

AF

de novo

47,XY,dup(21)(q22.2q21.1),+r[18]/ 46,XY,dup(21)(q22.2q21.1)[32]

r(19)(::p13.11→q13.2::)* sSMC derived from a maternal chromosome 19

different FISH probes, micro satellite analysis; UPD-test

see below

{8} case 3 {42}

Amniocentesis due to advanced maternal age; Baby born by cesarean section at 40th week without complications, with hypotonia, dysmorphic craniofacial features including microcephaly, hypertelorism, upward slanting palpebral fissures, deep palmar and plantar crease; delayed myelinisation, psychomotor development moderately delayed at 9m. No Down syndrome features, which is in concordance with the lack of the DSCR.